The incidence of pancreatic cancer throughout the world has steadily increased over the past 20 years and the disease is now the fourth and fifth most common cause of cancer death in men and women, respectively, in the United States. Among possible etiological factors, diabetes seems to be prominent (an association between the two diseases has been discussed for a century) in that it appears to be a predisposing factor for pancreatic cancer development. We propose to define this relationship in an animal model we have been developing since 1974 and which in many aspects resembles human pancreatic cancer. We have found exocrine pancreatic cancer to primarily originate from ductular cells that represent pancreatic stem cells, from which islet cells also develop. It has been well-documented experimentally that in induced diabetes in animals [by alloxan and streptozotocin (SZ)] the newly formed islets originate from ductular cells. It is also known that in untreated adult diabetics new islet cell formation occurs from the ductules. Since this islet cell neoformation is associated with ductular cell proliferation, it is highly possible that cellular proliferation is associated with an increased risk of pancreatic ductular cell carcinoma, as has been shown experimentally. If so, since insulin seems to suppress the body's demand for formation of new islets, and consequently, ductular cell proliferation, the risk of cancer development can be overcome by insulin treatment of diabetics, who otherwise do not require insulin. To examine these possibilities we propose an experiment in which the effect of a pancreatic carcinogen will be examined in animals made diabetic by SZ. We plan to administer the carcinogen at the peak of islet cell regeneration (from ductules) in response to SZ-caused islet destruction, which according to our study starts 2 days and peaks 5 days after SZ. Since exogenous insulin was shown by us to control diabetes and to inhibit ductular cell hyperplasia (and islet cell neogenesis), we will also examine whether or not insulin treatment after SZ will prevent pancreatic cancer induction. The results of the proposed study will have great implications for adult onset diabetics and for determining the preventive regimen.